Self-recognizing And Stimulus-responsive Carrier-free Metal-coordinated Nanotheranostics For Magnetic Resonance/photoacoustic/fluorescence Imaging-guided Synergistic Photo-chemotherapy

Cancer is a major threat to human health.Non-invasive chemotherapy,phototherapy,gene therapy and immunotherapy have opened a new chapter in cancer therapy compared with the traumatic treatment brought by surgery.Conventional antitumor drugs have always faced many bottlenecks.Examples include rapid blood/kidney clearance,low tumor accumulation,nonspecific biodistribution,and systemic toxicity.Nowadays,carrier-based nanodrug delivery systems have been widely developed to overcome the above defects,the drug-loading of such systems is low,and there are still some obstacles,including the lack of targeted specificity,poor biodegradability,and unavoidable toxicity of the carrier.Thus,it is urgent to develop a actively targeted carrier-free nanodrug with high drug-loading and biosecurity.However,such carrier-free nanodrugs are easy to disassemble in the bloodstream,leading to premature drug release and unpredictable side effects.In addition,due to the heterogeneity and individual differences of tumors,the delivery process of nanodrugs in vivo is difficult to track,the accumulation in tumor sites is not clear,and the metabolic mechanism has not been clarified.Therefore,in order to achieve safe and effective tumor treatment,enhancing the structural stability of nanodrugs in the blood circulation,and observing their delivery in vivo in real-time through imaging techniques can effectively improve the bioavailability and reduce the toxic and side effects on normal tissues.Herein,we designed a carrier-free nanotheranostic agent based on photosensitizer indocyanine green(ICG)and chemotherapy drug methotrexate(MTX),aiming to improve the dual-drug loading.Meanwhile,the carrier-free nanotheranostics were endowed with self-recognition ability while avoiding exogenous targeting ligands.Nevertheless,the weak interactions between ICG and MTX molecules alone are not enough to construct stable nanostructures.Relying on supramolecular chemistry,ferric(FeⅢ)ions were introduced into ICG-MTX by coordination effect.The introduction of coordination interaction not only enhanced the stability of the nanostructures,but also provided additional magnetic resonance imaging function for the nanotheranostics.Moreover,the drug-loading of the nanotheranostics(ICG-MTX-FeⅢ)was up to-94 wt%.ICG-MTX-FeⅢ exhibited a long circulating half-life in the blood and could achieve targeted on-demand drug release under the dual-stimulation of lysosomal acidity in vivo and near-infrared laser in vitro.More importantly,ICG-MTX-FeⅢ could self-recognize the cancer cells and selectively target tumors,reducing side effects on normal tissues and organs.ICG-MTX-FeⅢ showed strong synergistic photo-chemotherapeutic effects and achieved complete tumor ablation under the precise guidance of magnetic resonance/photoacoustic/fluorescence imaging.Besides,both ICG and MTX are approved by Food and Drug Administration,and FeⅢ ions have high biosecurity.Therefore,the self-recognizing and stimulus-responsive carrier-free metal-coordinated nanotheranostics may have a broad application prospect in tumor treatment and diagnosis.